Pathologic myopia, or extreme nearsightedness, is a leading cause of blindness worldwide, particularly in Asian populations. It has been estimated that up to 2.3 billion people are myopic globally (with a prevalence as high as 80% in Southeast Asia) and the numbers are rising. Although minimal levels of near-sightedness are considered a minor inconvenience, high (pathologic) myopia can lead to irreversible vision loss. Myopia is often due to excessive eye elongation. Pathologic myopia is due to progressive, lifelong and extreme eye elongation with subsequent eye wall (sclera) thinning, which allows for localized outpouchings (called staphyloma). Development of staphyloma often immediately precedes irreversible vision loss. The long-term goal of my laboratory is to stunt myopia progression and identify patients at risk of vision loss. Although scleral collagen dysfunction has been proposed to underlie staphyloma formation, there is no safe, effective therapy to fortify the eye wall collagen or a standard quantitative method to assess for staphyloma progression. We now have a group of chemicals (beta-nitroalcohols or BNAs) that can stiffen tissue by crosslinking collagen in animal models and imaging technology that can assess the eye wall in vivo and potentially monitor scleral strength and pliability in both animals as well as human patients. Taken together, we can now test whether BNAs can stunt physiologic as well as pathologic eye elongation as assessed by in vivo imaging in animal models. We also hypothesize that the same imaging modalities can be used to identify myopic patients at risk of vision loss. Specifically, we propose to employ various BNAs to crosslink scleral collagen to act as a mortar, stiffening the eye wall. In Aim 1, we test which BNAs effectively and safely stunt physiologic eye elongation in growing adolescent rabbits and guinea pig pups. In Aim 2, we will apply the most effective BNAs in an attempt to stunt pathologic eye elongation in a guinea pig model of myopia, recently shown capable of forming staphyloma. We will phenotype these animals using multimodal imaging established in our pilot work. These imaging modalities will be used concurrently in Aim 3 where we perform natural history studies in highly myopic patients with and without staphyloma to elucidate a quantitative measure of susceptibility to staphyloma development/progression and key time points or anatomic locations toward which therapy should be directed. Our goal is to identify the type of patients who would most benefit from BNA treatment. We hypothesize that crosslinking the component collagen will stiffen the eye wall, thereby halting myopia progression and avoiding permanent vision loss and that at-risk patients can be identified by the pliability of staphyloma. This work has the potential to aid millions of pathologic myopia patients with weakened staphyloma, otherwise destined for permanent vision loss. Fortifying eyes that have prematurely reached adult eye length, but have yet to reach physical maturity, may allow billions of young patients to avoid myopia altogether.